autosomal recessive severe congenital neutropenia due to G6PC3 deficiency

Summary

autosomal recessive severe congenital neutropenia due to G6PC3 deficiency (MONDO:0012930) is a disease caused by G6PC3 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: G6PC3 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 428

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		57	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive severe congenital neutropenia due to G6PC3 deficiency
Mondo ID	MONDO:0012930
OMIM	612541
Orphanet	331176
DOID	DOID:0112136
UMLS	C2751630
MedGen	414066
GARD	0017511
Is cancer (heuristic)	no

Also known as: autosomal recessive severe congenital neutropenia due to G6PC3 deficiency · neutropenia, severe congenital 4, autosomal recessive · neutropenia, severe congenital, 4, autosomal recessive · SCN4 · severe congenital neutropenia type 4 · severe congenital neutropenia-pulmonary hypertension-superficial venous angiectasis syndrome

Data availability: 428 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › autosomal recessive severe congenital neutropenia › autosomal recessive severe congenital neutropenia due to G6PC3 deficiency

Related subtypes (5): Kostmann syndrome, congenital neutropenia-myelofibrosis-nephromegaly syndrome, autosomal recessive severe congenital neutropenia due to JAGN1 deficiency, autosomal recessive severe congenital neutropenia due to CSF3R deficiency, autosomal recessive severe congenital neutropenia due to CXCR2 deficiency

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

428 retrieved; paginated sample, class counts are floors:

200 likely benign, 147 uncertain significance, 39 pathogenic, 20 conflicting classifications of pathogenicity, 11 likely pathogenic, 6 benign, 4 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1004638	NM_138387.4(G6PC3):c.758_781del (p.Arg253_Gly260del)	G6PC3	Pathogenic	criteria provided, single submitter
1037	NM_138387.4(G6PC3):c.758G>A (p.Arg253His)	G6PC3	Pathogenic	criteria provided, multiple submitters, no conflicts
1038	NM_138387.4(G6PC3):c.554T>C (p.Leu185Pro)	G6PC3	Pathogenic	no assertion criteria provided
1039	NM_138387.4(G6PC3):c.141C>G (p.Tyr47Ter)	G6PC3	Pathogenic	no assertion criteria provided
1040	NM_138387.4(G6PC3):c.784G>C (p.Gly262Arg)	G6PC3	Pathogenic	no assertion criteria provided
1042	NM_138387.4(G6PC3):c.346A>G (p.Met116Val)	G6PC3	Pathogenic	no assertion criteria provided
1066709	NM_138387.4(G6PC3):c.677+1G>A	G6PC3	Pathogenic	criteria provided, single submitter
1342134	NM_138387.4(G6PC3):c.765_766del (p.Ala257fs)	G6PC3	Pathogenic	criteria provided, multiple submitters, no conflicts
1430600	NM_138387.4(G6PC3):c.218+1G>A	G6PC3	Pathogenic	criteria provided, single submitter
1451174	NM_138387.4(G6PC3):c.635del (p.Leu212fs)	G6PC3	Pathogenic	criteria provided, single submitter
1705639	NM_138387.4(G6PC3):c.144C>A (p.Tyr48Ter)	G6PC3	Pathogenic	criteria provided, multiple submitters, no conflicts
189781	NM_138387.4(G6PC3):c.130C>T (p.Pro44Ser)	G6PC3	Pathogenic	criteria provided, multiple submitters, no conflicts
189782	NM_138387.4(G6PC3):c.210del (p.Phe71fs)	G6PC3	Pathogenic	criteria provided, multiple submitters, no conflicts
189783	NM_138387.4(G6PC3):c.829C>T (p.Gln277Ter)	G6PC3	Pathogenic	criteria provided, single submitter
189784	NM_138387.4(G6PC3):c.935dup (p.Asn313fs)	G6PC3	Pathogenic	no assertion criteria provided
2034287	NM_138387.4(G6PC3):c.765del (p.Ala257fs)	G6PC3	Pathogenic	criteria provided, single submitter
2138049	NM_138387.4(G6PC3):c.481C>T (p.Arg161Ter)	G6PC3	Pathogenic	criteria provided, multiple submitters, no conflicts
2427235	NC_000017.10:g.(?42151508)(42153411_?)del	G6PC3	Pathogenic	criteria provided, single submitter
2736600	NM_138387.4(G6PC3):c.131C>T (p.Pro44Leu)	G6PC3	Pathogenic	criteria provided, single submitter
2750293	NM_138387.4(G6PC3):c.63G>A (p.Trp21Ter)	G6PC3	Pathogenic	criteria provided, single submitter
2760959	NM_138387.4(G6PC3):c.246G>A (p.Trp82Ter)	G6PC3	Pathogenic	criteria provided, single submitter
2767618	NM_138387.4(G6PC3):c.218+2T>C	G6PC3	Pathogenic	criteria provided, single submitter
2769107	NM_138387.4(G6PC3):c.376del (p.Ile125_Met126insTer)	G6PC3	Pathogenic	criteria provided, single submitter
2777278	NM_138387.4(G6PC3):c.210_213del (p.Phe71fs)	G6PC3	Pathogenic	criteria provided, single submitter
2832417	NM_138387.4(G6PC3):c.267C>G (p.Tyr89Ter)	G6PC3	Pathogenic	criteria provided, single submitter
2837752	NM_138387.4(G6PC3):c.3G>T (p.Met1Ile)	G6PC3	Pathogenic	criteria provided, single submitter
2838564	NM_138387.4(G6PC3):c.575dup (p.Met192fs)	G6PC3	Pathogenic	criteria provided, single submitter
2853520	NM_138387.4(G6PC3):c.163del (p.Ile55fs)	G6PC3	Pathogenic	criteria provided, single submitter
2858133	NM_138387.4(G6PC3):c.62G>A (p.Trp21Ter)	G6PC3	Pathogenic	criteria provided, single submitter
30874	NM_138387.4(G6PC3):c.778G>C (p.Gly260Arg)	G6PC3	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
G6PC3	Definitive	Autosomal recessive	autosomal recessive severe congenital neutropenia due to G6PC3 deficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
G6PC3	Orphanet:331176	Severe congenital neutropenia due to G6PC3 deficiency

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
G6PC3	HGNC:24861	ENSG00000141349	Q9BUM1	Glucose-6-phosphatase 3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
G6PC3	Glucose-6-phosphatase 3	Hydrolyzes glucose-6-phosphate to glucose in the endoplasmic reticulum.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Phosphatase	1	83.9×	0.012

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
G6PC3	Phosphatase	yes	3.1.3.9	PAP2/HPO, Glucose-6-phosphatase, PAP2/HPO_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adenohypophysis	1
pituitary gland	1
right adrenal gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
G6PC3	278	ubiquitous	marker	adenohypophysis, pituitary gland, right adrenal gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
G6PC3	1,742

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
G6PC3	Q9BUM1	92.79

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Severe congenital neutropenia type 4 (G6PC3)	1	11420.0×	2e-04	G6PC3
Gluconeogenesis	1	439.2×	0.002	G6PC3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glucose-6-phosphate transport	1	2808.7×	0.001	G6PC3
glucose 6-phosphate metabolic process	1	1296.3×	0.001	G6PC3
gluconeogenesis	1	324.1×	0.003	G6PC3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
G6PC3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
G6PC3	3.1.3.9	glucose-6-phosphatase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	G6PC3
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
G6PC3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.